title: Protective roles for caspase-8 and cFLIP in adult homeostasis.
abstract: Caspase-8 or cellular FLICE-like inhibitor protein (cFLIP) deficiency leads to embryonic lethality in mice due to defects in endothelial tissues. Caspase-8(-/-) and receptor-interacting protein kinase-3 (RIPK3)(-/-), but not cFLIP(-/-) and RIPK3(-/-), double-knockout animals develop normally, indicating that caspase-8 antagonizes the lethal effects of RIPK3 during development. Here, we show that the acute deletion of caspase-8 in the gut of adult mice induces enterocyte death, disruption of tissue homeostasis, and inflammation, resulting in sepsis and mortality. Likewise, acute deletion of caspase-8 in a focal region of the skin induces local keratinocyte death, tissue disruption, and inflammation. Strikingly, RIPK3 ablation rescues both phenotypes. However, acute loss of cFLIP in the skin produces a similar phenotype that is not rescued by RIPK3 ablation. TNF neutralization protects from either acute loss of caspase-8 or cFLIP. These results demonstrate that caspase-8-mediated suppression of RIPK3-induced death is required not only during development but also for adult homeostasis. Furthermore, RIPK3-dependent inflammation is dispensable for the skin phenotype.
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Weinlich
authors.forename: Andrew
authors.initials: A
authors.lastname: Oberst
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Dillon
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Janke
authors.forename: Sandra
authors.initials: S
authors.lastname: Milasta
authors.forename: John R
authors.initials: JR
authors.lastname: Lukens
authors.forename: Diego A
authors.initials: DA
authors.lastname: Rodriguez
authors.forename: Prajwal
authors.initials: P
authors.lastname: Gurung
authors.forename: Chandra
authors.initials: C
authors.lastname: Savage
authors.forename: Thirumala D
authors.initials: TD
authors.lastname: Kanneganti
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
mesh_terms: D000818:Animals; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D020895:Enterocytes / Q000166:cytology; D006706:Homeostasis / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D014409:Tumor Necrosis Factor-alpha; D013629:Tamoxifen; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D053181:Caspase 8